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Macroglobulinemia of Waldenstrom(WM) - Plasma Cell Disorders


Macroglobulinemia of Waldenstrom(WM) is a cancer of the B lymphocytes/ B-cells (a type of white blood cell). Such cancer is called lymphoplasmacytic lymphoma. It is associated with the overproduction of proteins called IgM antibodies and belongs to a group of disorders called lymphoproliferative diseases.

Plasma cells develop from B lymphocytes (B cells), a type of white blood cell that is made in the bone marrow. Normally, when bacteria or viruses enter the body, some of the B cells will change into plasma cells. The plasma cells make a different antibody to fight each type of bacteria or virus that enters the body, to stop infection and disease.

Causes

The cause of the overproduction of the IgM antibody is unknown. Overproduction of IgM causes the blood to become too thick. This is called hyperviscosity. It makes it harder for blood to flow through small blood vessels.


Symptoms

People with WM may have no symptoms for years after diagnosis. There does not appear to be a correlation between the level of monoclonal IgM and the degree of symptoms. Patients with similar laboratory test results may show markedly different types and degrees of symptoms.

The symptoms and complications of WM that eventually appear stem from two main factors
  • Marrow infiltration by abnormal cells.
  • The properties of the monoclonal IgM, which cause blood vessel impairment and can cause organ damage.
The most common early symptoms of WM are fatigue and weakness due to anemia. Patients may also experience:
  • Unintentional weight loss
  • Abnormal bleeding, especially from the nose and gums.
  • Enlarged lymph nodes.
  • Enlarged spleen and liver.
  • Blurred or decreased vision
  • Peripheral neuropathy (changes in the nerves affecting the hands, feet, fingers, toes, ears, or nose) manifested by:
    • Numbness or tingling
    • Burning pain
Additional symptoms that may be associated with this disease:
  • Easy bruising of the skin
  • Rash
  • Nosebleeds (epistaxis)
  • Unintentional weight loss
  • Vision loss in one eye
  • Headache
  • Dizziness
  • Mental status changes
  • Swollen glands
  • Flank pain
  • Bluish skin discoloration
  • Fingers that change color upon pressure
Tests and Diagnose

WM is suspected when a blood test, performed as part of an annual exam, shows an elevated total protein value. WM is diagnosed if additional blood and marrow tests reveal the presence of monoclonal IgM and evidence of monoclonal B-lymphocytes in marrow.

Tests used to make the diagnosis of WM are:

A physical examination may reveal a swollen spleen, liver, and lymph nodes. An eye exam may show enlarged veins in the retina or retinal bleeding (hemorrhages).

A CBC shows a low number of red bloods and platelets. A blood chemistry shows evidence of kidney disease. A serum viscosity test can tell if the blood has become thick. Symptoms usually occur when the blood is four times thicker than normal.

A test called serum protein electrophoresis shows an increased amount of the IgM antibody. Levels seen in Waldenstrom's macroglobulinemia are generally greater than 3 g/dL.

Bone lesions are very rare. If they are present, a bone marrow examination will show cells that resemble both lymphocytes and plasma cells.

Blood tests to detect the presence of monoclonal IgM.

Flow cytometry for immunophenotyping of the lymphocytes. (The lymphocytes associated with WM are characterized by cell markers, or antigens on the surface of the cell, that include: CD19, CD20, CD22 and CD79.)

Bone marrow analysis to detect the infiltration of abnormal B-lymphocytes in marrow.

Additional tests that may be done:
  • 24-hour urine protein
  • Total protein
  • Serum globulin electrophoresis
  • Immunofixation in urine
  • T (thymus derived) lymphocyte count

Other typical findings from blood tests at diagnosis include:
  • LI>Anemia (red count lower than normal) is present in the majority of WM patients at diagnosis.Hemoglobin and hematocrit readings are often low, even if the absolute quantities are normal or near-normal, because there is an increase in plasma (the fluid portion of the blood).
  • Although there may be a reduction in total white cell count, it is usually normal. However, an increase in lymphocytes (one type of white cell) is present. Also, monoclonal B-lymphocytes can be detected by flow cytometry in almost all patients.
  • Many patients have elevated serum beta-2-microglobulin (B2M) at diagnosis.
  • Uninvolved immunoglobulins (IgG, IgA, IgD and IgE) are usually somewhat decreased.
  • Cholesterol is usually low, often under 100.
Various blood cell chromosomal abnormalities have been observed in WM patients. However, no one particular chromosomal abnormality has been identified in patients with this disease.



Related Complications

Hyperviscosity syndrome

The large size of the monoclonal IgM molecule can cause a circulatory condition called hyperviscosity syndrome in about 10 to 30 percent of WM patients. Hyperviscosity syndrome may result in bleeding, headache, dizziness and hearing or visual problems, and can be life threatening.


Cold agglutinin disease

About 10% of WM patients have an acquired hemolytic anemia called cold agglutinin disease. In cold agglutinin disease monoclonal IgM causes the destruction of red blood cells when a patient is in an environment where temperatures are low. Raynaud's phenomenon, exemplified by signs of poor circulation in the fingers is an indicator of cold agglutinin disease. Red cell circulation in blood vessels in the skin of the nose, ears, fingers and toes may be affected by the cold air temperatures.


Cryoglobulinemia

Ten to 20 percent of patients with WM also develop cryoglobulinemia, a condition that is made worse by exposure to cold temperatures. Cryoglobulinemia is manifested by Raynaud's phenomenon, kidney problems and purpura (purplish or red-brown discoloration of the skin).


Other rare complications

Vision problems, Gastrointestinal bleeding, Changes in mental function, possibly leading to coma, Congestive heart failure, Pulmonary complications, skin lesions (including hives, ulcers and flesh-colored papules), renal complications and bone involvement are rare but possible.



Treatments

Plasmapheresis (plasma exchange) removes unwanted substances from the blood. In macroglobulinemia, it removes or reduces the high level of IgM, and is used to quickly control the symptoms caused by blood thickening.

Drug therapy may include steroids, Leukeran, Alkeran, Cytoxan, fludarabine, or rituximab.

Patients who have a low number of red or white blood cells or platelets may need transfusions or antibiotics.

Chemotherapy and combination chemotherapies. The mainstays of first line chemotherapy for WM are alkylating agents, such as chlorambucil, and purine nucleoside analogs, such as fludarabine and cladribine, given singly, in combination, or in sequence.

Monoclonal antibody therapy. Alemtuzumab (Campath®) and rituximab (Rituxan®), types of monoclonal antibody therapies, can locate tumor cells and either kill or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy stop cancer cells from dividing via different mechanisms. Combining chemotherapy and monoclonal antibody therapy may kill more cancer cells.

Bortezomib. Bortezomib (Velcade®) is a proteasome inhibitor approved for the treatment of myeloma. This drug may stop the growth of cancer by blocking the enzymes necessary for tumor cell growth. It is currently being studied in clinical trials with patients with previously untreated or relapsed WM.

Stem cell transplantation. Stem cell transplantation is another potential emerging treatment for WM, although current data is limited as far as its effectiveness. Peripheral blood stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy.

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